The metabolic and cardiovascular sequelae of obesity constitute a major financial and public health burden. Increased cardiovascular risk in obesity is directly related to metabolic dysregulation, key features of which include abnormalities in energy homeostasis and insulin resistance. The effectiveness of weight loss efforts to reduce cardiometabolic risk in obesity is limited due to high weight gain recidivism. Therefore, interventions that directly target metabolic fitness in obesity represent an important area of investigation. Evidence in experimental models and our preliminary data in humans suggest that the cyclic guanylate monophosphate pathway (cGMP) is a critical mediator of insulin resistance and energy homeostasis. Increased cGMP signaling raises resting energy expenditure and provides resistance to obesity and diabetes. Cyclic GMP also stimulates mitochondrial biogenesis and oxidative capacity in skeletal muscle. Phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil prevent the degradation of cGMP. These medications are well-tolerated and improve glucose metabolism, but have not been comprehensively tested as a target for obesity-related cardiometabolic dysfunction in humans. We propose a randomized, placebo-controlled study to examine the cardiometabolic effects of PDE5 inhibition in obese prediabetic individuals. Participants will receive tadalafil 20 mg per day or placebo for 12 weeks. Aim 1 will examine the effect of chronic PDE5 inhibition on resting and exercise energy expenditure using a metabolic chamber. In Aim 2, we will test the effect of PDE5 inhibition on insulin sensitivity and secretion. We will also assess body composition, quality of life, and sexual function. A Secondary Aim will examine the effect of PDE5 inhibition on cGMP sensitivity and circulating mediators of diabetes risk. The proposed study will be the first large comprehensive evaluation of PDE5 inhibition in a population at high risk of cardiovascular disease. Our endpoints were selected to provide highly relevant clinical outcomes and mechanistic insight into the cardiometabolic effects of cGMP action. Therapy that improves metabolic fitness independent of weight loss would represent an important advance in the effort to reduce cardiovascular risk in obesity.